Neurotransmitter tryptophan metabolism plus – kynurenine test (urine)

Tryptophan is an amino acid that the body cannot make itself and takes in with food. Only a small part becomes serotonin and melatonin; around 95% is broken down via the kynurenine pathway, mainly in the liver (PubMed 28469468). The liver enzyme (TDO) is stimulated by cortisol, among other things, and the enzyme IDO in other tissues by inflammatory messengers (PubMed 28469468, PubMed 32153576).

A low value in urine can therefore be related to diet, absorption in the gut or increased breakdown. It is not proof of a deficiency in the brain. Whether it plays a role in your situation is something to discuss with the ORY expert team or with your doctor or naturopath, for example from the ORY expert network.

Kynurenine is the first stable intermediate in the breakdown of tryptophan. The IDO activity is calculated in the report from the ratio of kynurenine to tryptophan. The enzyme IDO is stimulated mainly by the inflammatory messenger interferon-gamma; in research, a high ratio is therefore regarded as an indication of activated immune defence (PubMed 32153576, PubMed 28751584).

Exercise, diet and cortisol also influence the kynurenine pathway (PubMed 28751584, PubMed 28469468). An elevated value shows increased breakdown but does not say where in the body or why. A low kynurenine value has no generally accepted meaning.

Two branches arise from kynurenine: kynurenic acid and, via 3-OH-kynurenine, quinolinic acid. In the brain, kynurenic acid inhibits NMDA receptors and is considered protective; quinolinic acid stimulates the same receptors and can damage nerve cells at high concentrations (PubMed 16181118). The enzyme KMO helps decide which branch predominates; a KMO activity is calculated for this in the report.

Important: kynurenic acid hardly crosses the blood-brain barrier (PubMed 16181118). Urine values describe breakdown throughout the body, not the situation in the brain. At the end of the pathway is NAD, a building block of energy metabolism (PubMed 28469468).

Serotonin is formed from tryptophan, around 95% of it in cells of the gut lining (PubMed 34360695). Dopamine, adrenaline and noradrenaline are catecholamines from the kidney, adrenal gland and sympathetic nervous system (PubMed 8504632, PubMed 12649306). They rise with stress and physical exertion (PubMed 8597393); in addition, the report states the noradrenaline/adrenaline ratio.

High or low values describe excretion at the time of sampling and are considered together with tryptophan breakdown. They do not show the messengers in the brain (PubMed 32479926).

GABA (gamma-aminobutyric acid) is the main inhibitory, i.e. calming, messenger in the brain (PubMed 26500584). However, GABA also occurs outside the brain and is produced by gut bacteria, for example. According to a review, whether and how much GABA is exchanged between blood and brain has so far been studied with contradictory results (PubMed 26500584).

A low or high GABA value in urine therefore describes excretion, not the amount in the brain. There is no established urine test for a "GABA deficiency"; whether a value plays a role in your situation is something to discuss with the ORY expert team or with your doctor or naturopath, for example from the ORY expert network.

Glutamate is the main excitatory messenger in the brain and at the same time a building block of proteins and a metabolite throughout the body. The blood-brain barrier tightly regulates glutamate levels in the brain (PubMed 28828617); according to a review, glutamate from food, for example as a flavour enhancer, does not raise the concentration in the brain (PubMed 30508818).

The urine value therefore shows how much glutamate the body excretes, for example depending on diet and metabolism. An elevated value is not an indication of "too much excitation in the brain".

From the amino acids phenylalanine and tyrosine the body forms dopamine, noradrenaline and adrenaline. As cofactors, the report evaluates indications of vitamin B6 (via cystathionine), vitamin B12 (via methylmalonic acid) and vitamin B3 (niacin, nicotinamide, NAD); in addition there is a calculated estimate of tetrahydrobiopterin (BH4). Methylmalonic acid rises in vitamin B12 deficiency and is used in practice for assessment (PubMed 23301732, PubMed 28660890).

The other cofactors are indirect markers in urine. An abnormal value is an indication, not proof of a vitamin deficiency; a suspected B12 deficiency should be assessed by a doctor using blood values.

Methylation: S-adenosylmethionine (SAM), betaine and choline supply methyl groups for many metabolic reactions; the SAM/SAH ratio is reported as methylation capacity. NO stress and energy metabolism: citrulline, citrate, lactate, pyruvate, suberic acid and carnitine are intermediates of the metabolism of the cell's power plants (mitochondria) and of nitric oxide metabolism. Gut bacteria: trimethylamine (TMA) and trimethylamine N-oxide (TMAO) are formed when gut bacteria convert choline and carnitine from food; TMAO is studied in cardiovascular research (PubMed 32762536).

There are no guidelines for using these urine markers in an individual. They depend strongly on diet, exercise and time of day and are only looked at in context.

Neopterin is produced by immune cells (macrophages) when they are activated by interferon-gamma. Measurement in urine therefore gives an indication of activation of cellular immune defence, for example in viral infections or inflammatory diseases (PubMed 12003349, PubMed 29949851).

Neopterin and IDO activity are stimulated by the same messenger and are therefore considered together (PubMed 32153576). An elevated value is non-specific: it does not show what causes the immune activation. Intense physical exertion can also change it (PubMed 29949851).

Tryptophan has two main routes: a small part becomes serotonin and then melatonin, while by far the largest part, around 95%, is broken down via the kynurenine pathway. At its end are vitamin B3 metabolism and NAD (PubMed 28469468). Along the way, substances are formed that regulate the immune system and act on nerve cells (PubMed 28751584).

How much tryptophan goes in which direction depends on inflammation, cortisol, diet and exercise, among other things; in studies, muscle training promotes the conversion of kynurenine to kynurenic acid (PubMed 28751584).

The kynurenine pathway is well described in research, and the kynurenine-to-tryptophan ratio as well as neopterin are used in studies as markers of immune activation (PubMed 32153576). For use in an individual, however, there are no generally accepted cut-offs or guidelines; the report states the reference ranges of the testing laboratory.

The values come from the whole body, mainly from the liver and immune cells (PubMed 28469468), and do not allow conclusions about the brain (PubMed 16181118). They show a snapshot that depends on diet, exercise, infections and stress on the day of sampling.

No, and this is the most important limitation of this test. Serotonin hardly crosses the blood-brain barrier; the serotonin pools in the brain and in the rest of the body are separate, and almost all serotonin outside the brain comes from cells of the gut lining (PubMed 32479926, PubMed 34360695). Dopamine in urine is formed to a large extent in the kidney itself from its precursor L-DOPA (PubMed 8504632). Adrenaline and noradrenaline in urine come mainly from the adrenal glands and the sympathetic nervous system, i.e. from the body rather than the brain (PubMed 12649306). Whether GABA from the blood reaches the brain is still unclear (PubMed 26500584).

A review by authors from a test provider sees urinary neurotransmitters as a possible marker of nervous system activity (PubMed 20696183). There is so far no independent evidence that a single urine value reflects the messengers in the brain or a person's mood. The report therefore shows what your body excretes at the time of sampling, not the "serotonin level in your head".

In research, the measured messengers are associated with the following areas, with varying strength of evidence:

• Stress load and inner tension: under stress, the adrenal medulla and the sympathetic nervous system are activated and release adrenaline and noradrenaline (PubMed 8597393). In one study, workers with high job demands had more catecholamines in 24-hour urine (PubMed 23892640). Observed in studies, not meaningful for the individual case.
• Drive and motivation: dopamine in the brain is involved in activation, willingness to exert effort and persistence with tasks (PubMed 23141060). Well established for the brain; the urine value does not reflect this.
• Mood and sleep: in the brain, serotonin is involved in mood, sleep and anxiety (PubMed 32479926). That a deficiency in the body explains low mood is not supported (PubMed 35854107).
• Trouble falling or staying asleep: stress and sleep influence each other, among other things via the stress axis (PubMed 35822937). Well described, but not measurable via urine values.
• Tiredness and exhaustion with inflammation: in chronic inflammation and serious illness, increased tryptophan breakdown has been observed together with tiredness (PubMed 32153576). Observed in studies, not transferable to healthy people.

These are associations from studies, not causes in an individual person. A laboratory test cannot explain complaints and does not provide a diagnosis. Persistent complaints belong in a medical assessment first.

If you have thoughts of harming yourself or feel you are in an acute crisis: in Germany, the TelefonSeelsorge can be reached free of charge around the clock on 0800 111 0 111. In acute danger, call the emergency number 112.

With sudden bouts of a racing heart with sweating, severe headaches and high blood pressure, the first step is a doctor's practice. To investigate a hormone-producing disorder of the adrenal gland, the guideline recommends measuring metanephrines, not a neurotransmitter test (PubMed 24893135). Chest pain, shortness of breath or paralysis are an emergency: call 112.

If low mood, lack of drive, anxiety or severe sleep problems persist for weeks, this belongs in a GP, psychotherapy or psychiatry practice first. A urine test does not replace this assessment. Never stop prescribed medication on your own because of a laboratory value.

This page does not give treatment recommendations. Whether a result means anything at all and which steps make sense depends on your overall situation: complaints, previous findings, medication, sleep and stress. Whether tryptophan breakdown can be changed in a targeted way in an individual, and whether this improves complaints, has not been established so far (PubMed 28751584).

What makes sense for you belongs in a conversation with the ORY expert team or with your doctor or naturopath, for example from the ORY expert network. Do not take preparations that influence messengers or hormones on your own because of a laboratory value, especially not alongside prescribed medication.

According to the instructions: 48 hours before no preparations containing 5-HTP, tryptophan or other neurotransmitter precursors. 24 hours before no alcohol, no excessive physical exertion and no large amounts of bananas, avocados, nuts or other tryptophan-rich meals. On the day of sampling stay fasting until the sample; an acute illness or severe stress can distort the values.

The second morning urine is used as a midstream sample, at least 2–4 hours after the first urine, collected with the enclosed disposable gloves directly into the sample container up to the mark. Store the sample cool and dark and send it on the same day if possible, preferably Monday to Thursday, not on Fridays or before public holidays. Only pause prescribed medication after talking to your doctor.

The analysis usually takes 7–21 days from the time the sample arrives at the laboratory. As soon as the report is ready, you will be notified. A 10-minute results consultation with the ORY expert team is available on request.

Neurotransmitter tryptophan metabolism plus costs €375 including VAT, shipping and return postage.

Statutory health insurance in Germany generally does not cover urine analyses you order yourself. With private insurance, reimbursement may be possible; how it works is described under "Reimbursement by private insurance".

Neurotransmitter Basic (€105) measures serotonin and catecholamines, Neurotransmitter Plus (€185.90) also GABA and glutamate. Neurotransmitter tryptophan metabolism (€305) combines serotonin and catecholamines with the kynurenine pathway, IDO and KMO activity and neopterin. Neurotransmitter tryptophan metabolism plus (€375) adds GABA, glutamate, catecholamine precursors, cofactors, methylation and energy metabolism. For the course of stress hormones over the day there is the cortisol day profile (€155), for several areas together the stress axis & sleep-wake rhythm lab package (€762).

Which scope makes sense for you can be clarified in the free initial consultation.